About | 16p12.2 deletion study - The Girirajan Laboratory

The 16p12.2 deletion (previously termed 16p12.1 deletion) is significantly associated with neurodevelopmental disease, and occurs at a frequency of 1 in 2,000 live births. The primary 16p12.2 deletion spans 7 genes of interest: PDZD9, UQCRC2, C16orf52, VWA3A, EEF2K, POLR3E, and CDR2 (right figure).

Individuals with the deletion have a sensitized genomic background rendering them vulnerable to multiple neurodevelopmental disorders such as intellectual disability, autism, and epilepsy. We are currently studying the 16p12.2 deletion as a paradigm to understand the complex genetics of developmental disorders. We hypothesize that genetic variants near or within the CNV interval and/or at a second site elsewhere in the genome contribute to the phenotypic outcome of disorders association with the deletion. Because the 16p12.2 deletion is inherited from parents in >90% of cases, assessing family history is essential.

A wide array of clinical features has been associated with the 16p12.2 deletion. Affected individuals may exhibit intellectual disability/developmental delay, speech delay, autism-like features, sleep disorders, hypotonia, craniofacial abnormalities, growth retardation, microcephaly, and cardiac disease. Furthermore, seizure disorders are present and may manifest in several forms including West Syndrome, febrile seizures, or seizure-like episodes. Psychiatric and behavioral abnormalities have also been documented. Individuals carrying the 16p12.2 deletion do not present a common facial gestalt and do not share identical clinical presentation, which indicates that this deletion is non-syndromic.

Most genomic disorders are the result of non-allelic homologous recombination (NAHR) between large (larger than 10kb) and highly similar sequences, called segmental duplications. Several chromosomes are enriched in these types of DNA sequences, such as chromosome 16, most particularly its short arm (p=petite, 16p). This leads to a higher frequency of these rearrangements and therefore genomic disorders associated with this variation.

Study of the 16p12.2 deletion continues to be promising in understanding the variable clinical features associated with the disorder, and will lay a foundation to provide better treatment methods to patients in the years to come.

How to Participate

We are currently recruiting individuals with the 16p12.2 deletion and their family members for this study, and invite you to participate if your child or loved one has been affected by the deletion. The following link leads to an initial questionnaire, which we will use to obtain some preliminary information about you and your family members who carry the 16p12.2 deletion.

We estimate that the survey will take approximately 15 minutes to complete. We note that participation in this questionnaire is completely voluntary. All answers will be kept strictly confidential, and protected to the maximum extent as required by law.

After you complete the questionnaire, we will contact you directly with further information on our study. Your participation in this study will be very important in understanding the connections between genetic variants and the symptoms identified in individuals carrying the 16p12.2 deletion.

Link to 16p12.2 deletion questionnaire

Further Resources

Genetics Home Reference, US National Library of Medicine: 16p12.2 microdeletion

GeneReviews: 16p12.2 Recurrent Deletion

European Journal of Human Genetics: Clinical utility gene card for: 16p12.2 microdeletion

Additional reading

Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.
Pizzo L, Jensen M, Polyak A, Rosenfeld JA, Mannik K, Krishnan A, McCready E, Pichon O, Le Caignec C, Van Dijck A, Pope K, Voorhoeve E, Yoon J, Stankiewicz P, Cheung SW, Pazuchanics D, Huber E, Kumar V, Kember R, Mari F, Curró A, Castiglia L, Galesi O, Avola E, Mattina T, Fichera M, Mandarà L, Vincent M, Nizon M, Mercier S, Bénéteau C, Blesson S, Martin-Coignard D, Mosca-Boidron A, Caberg JH, Bucan M, Zeesman S, Nowaczyk MJM, Lefebvre M, Faivre L, Callier P, Skinner C, Keren B, Perrine C, Prontera P, Marle N, Renieri A, Reymond A, Kooy RF, Isidor B, Schwartz C, Romano C, Sistermans E, Amor DJ, Andrieux J, Girirajan S.

We assessed the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion and in autism probands carrying gene-disruptive variants compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features and higher burden of other hits compared with those with mild/no family history. The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

Phenotypic heterogeneity of genomic disorders and rare copy-number variants.
Girirajan S, Rosenfeld JA, Coe BP, Parikh S, Friedman N, Goldstein A, Filipink RA, McConnell JS, Angle B, Meschino WS, Nezarati MM, Asamoah A, Jackson KE, Gowans GC, Martin JA, Carmany EP, Stockton DW, Schnur RE, Penney LS, Martin DM, Raskin S, Leppig K, Thiese H, Smith R, Aberg E, Niyazov DM, Escobar LF, El-Khechen D, Johnson KD, Lebel RR, Siefkas K, Ball S, Shur N, McGuire M, Brasington CK, Spence JE, Martin LS, Clericuzio C, Ballif BC, Shaffer LG, Eichler EE.

Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copynumber variants of unknown clinical significance were eight times as likely to have developmental delay as were controls. Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant. Boys were more likely than girls to have disorders of phenotypic heterogeneity, and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring.

A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.
Girirajan S, Rosenfeld JA, Cooper GM, Antonacci F, Siswara P, Itsara A, Vives L, Walsh T, McCarthy SE, Baker C, Mefford HC, Kidd JM, Browning SR, Browning BL, Dickel DE, Levy DL, Ballif BC, Platky K, Farber DM, Gowans GC, Wetherbee JJ, Asamoah A, Weaver DD, Mark PR, Dickerson J, Garg BP, Ellingwood SA, Smith R, Banks VC, Smith W, McDonald MT, Hoo JJ, French BN, Hudson C, Johnson JP, Ozmore JR, Moeschler JB, Surti U, Escobar LF, El-Khechen D, Gorski JL, Kussmann J, Salbert B, Lacassie Y, Biser A, McDonald-McGinn DM, Zackai EH, Deardorff MA, Shaikh TH, Haan E, Friend KL, Fichera M, Romano C, Gécz J, DeLisi LE, Sebat J, King MC, Shaffer LG, Eichler EE.

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls. Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents. Probands were more likely to carry an additional large copy-number variant when compared to matched controls. The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.